tbuckley/cabot-search huggingface dataset:
In Situ Hydrogelation of Cellular Monolayers Enables Conformal Biomembrane Functionalization for Xeno‐Free Feeder Substrate Engineering
Authors: Chen‐Ying Chien, Jung‐Chen Lin, Ching‐Ying Huang, Chung‐Yao Hsu, Kai‐Chieh Yang, Saborni Chattopadhyay, Nicolas Nikoloutsos, Patrick Ching‐Ho Hsieh, Che‐Ming Jack Hu
Journal: Advanced Healthcare Materials (2022)

Abstract The intricate functionalities of cellular membranes have inspired strategies for deriving and anchoring cell‐surface components onto solid substrates for biological studies, biosensor applications, and tissue engineering. However, introducing conformal and right‐side‐out cell membrane coverage onto planar substrates requires cumbersome protocols susceptible to significant device‐to‐device variability. Here, a facile approach for biomembrane functionalization of planar substrates is demonstrated by subjecting confluent cellular monolayer to intracellular hydrogel polymerization. The resulting cell–gel hybrid, herein termed GELL (gelated cell), exhibits extraordinary stability and retains the structural integrity, membrane fluidity, membrane protein mobility, and topology of living cells. In assessing the utility of GELL layers as a tissue engineering feeder substrate for stem cell maintenance, GELL feeder prepared from primary mouse embryonic fibroblasts not only preserves the stemness of murine stem cells but also exhibits advantages over live feeder cells owing to the GELL's inanimate, non‐metabolizing nature. The preparation of a xeno‐free feeder substrate devoid of non‐human components is further shown with HeLa cells, and the resulting HeLa GELL feeder effectively sustains the growth and stemness of both murine and human induced pluripotent stem cells. The study highlights a novel bio‐functionalization strategy that introduces new opportunities for tissue engineering and other biomedical applications.
SOX4 promotes beige adipocyte-mediated adaptive thermogenesis by facilitating PRDM16-PPARγ complex
Authors: Huanming Shen, Ting He, Shuai Wang, Lingfeng Hou, Yixin Wei, Yunjia Liu, Chunli Mo, Zehang Zhao, WeiXin You, Huiling Guo, Boan Li
Journal: Theranostics (2022)

Brown and beige fat protect against cold environments and obesity by catabolizing stored energy to generate heat.This process is achieved by controlling thermogenesis-related gene expression and the development of brown/beige fat through the induction of transcription factors, most notably PPARγ.However, the cofactors that induce the expression of thermogenic genes with PPARγ are still not well understood.In this study, we explored the role of SOX4 in adaptive thermogenesis and its relationship with PPARγ.Methods: Whole transcriptome deep sequencing (RNA-seq) analysis of inguinal subcutaneous white adipose tissue (iWAT) after cold stimulation was performed to identify genes with differential expression in mice.Indirect calorimetry detected oxygen consumption rate and heat generation.mRNA levels were analyzed by qPCR assays.Proteins were detected by immunoblotting and immunofluorescence.Interaction of proteins was detected by endogenous and exogenous Co-IP.ChIP-qPCR, FAIRE assay and luciferase reporter assays were used to investigate transcriptional regulation.Results: SOX4 was identified as the main transcriptional effector of thermogenesis.Mice with either adipocyte-specific or UCP1 + cells deletion of SOX4 exhibited significant cold intolerance, decreased energy expenditure, and beige adipocyte formation, which was attributed to decreased thermogenic gene expression.In addition, these mice developed obesity on a high-fat diet, with severe hepatic steatosis, insulin resistance, and inflammation.At the cell level, loss of SOX4 from preadipocytes inhibited the development of beige adipocytes, and loss of SOX4 from mature beige adipocytes reduced the expression of thermogenesis-related genes and energy metabolism.Mechanistically, SOX4 stimulated the transcriptional activity of Ucp1 by binding to PPARγ and activating its transcriptional function.These actions of SOX4 were, at least partly, mediated by recruiting PRDM16 to PPARγ, thus forming a transcriptional complex to elevate the expression of thermogenic genes. Conclusion:SOX4, as a coactivator of PPARγ, drives the thermogenic gene expression program and thermogenesis of beige fat, promoting energy expenditure.It has important physiological significance in resisting cold and obesity.
A Pilot Study of Intralesional Injection of Triamcinolone Acetonide for Desmoid Tumors: Two-Year Outcomes
Authors: Benjamin K. Wilke, Hillary W. Garner, Joseph M. Bestic, Lori A. Chase, Michael G. Heckman, Jennifer J. Schoch, Steven Attia
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The purpose of this pilot study was to examine the clinical efficacy and safety of serial triamcinolone injections for the treatment of desmoid tumors. Patients and Methods: Nine patients were enrolled into this prospective study and underwent three serial ultrasound-guided triamcinolone injections (120 mg) at 6-week intervals. MRI was compared at baseline and every 6 months, out to 24 months. Safety and tolerability were assessed by clinical evaluation and questionnaires, including the 12-item short form survey (SF-12), visual analog scale (VAS), and desmoid patient-reported outcome (PRO) tool. Results: At 24 months, 8 (88.9%) patients demonstrated a reduction in the volume of their tumor while 1 (11.1%) enlarged. Median tumor volume change was −26.9% (−81.1% to 34.6%; P = 0.055) All 9 tumors remained stable based on World Health Organization criteria, whereas 2 (22.2%) demonstrated partial response based on RECIST. There was a significant decrease in the tumor:muscle postcontrast mean signal intensity ratio at 6 months (P = 0.008) and 24 months (P = 0.004). There was a similar decrease in the tumor:muscle T2 mean signal intensity ratio at 24 months (P = 0.02). We found no difference in the SF-12 and VAS scores, but there were significant improvements in the desmoid PRO. Conclusions: Treatment of desmoid tumors with serial triamcinolone injections appears safe and well tolerated by patients, with a 22% partial response based on RECIST. Further research is needed to confirm our results and determine factors predictive of response.
Development of functional nanomedicines for tumor associated macrophages-focused cancer immunotherapy
Authors: Xiao Wei, Jing Wang, Min Liang, Mingzhu Song
Journal: Theranostics (2022)

Clinical cancer immunotherapies are usually impeded by tumor immunosuppression driven by tumor associated macrophages (TAMs).Thus, TAMs can be considered as a promising therapeutic target for improved immunotherapy, and TAMs-focused molecular targeting agents have made ideal progress in clinical practice.Even so, most TAMs-targeting agents still cannot cover up their own shortcomings as free drugs.The emergence of multifunctional nanomaterials can expectedly endow these therapeutic cargoes with high solubility, favorable pharmacokinetic distribution, cell-specific delivery, and controlled release.Here, the underlying mechanisms of tumor immunosuppression caused by TAMs are first emphatically elucidated, and then the basic design of TAMs-focused immune-nanomedicines are discussed, mainly including diverse categories of nanomaterials, targeted and stimulus-responsive modifications, and TAM imaging in nanomedicines.A summary of current TAMs-targeting immunotherapeutic mechanisms based on functional nanomedicines for TAMs elimination and/or repolarization is further presented.Lastly, some severe challenges related to functional nanomedicines for TAMs-focused cancer immunotherapy are proposed, and some feasible perspectives on clinical translation of TAMs-associated anticancer immunonanomedicines are provided.It is hoped that, with rapid development of nanomedicine in cancer immunotherapy, TAMs-focused therapeutic strategies may be anticipated to become an emerging immunotherapeutic modality for future clinical cancer treatment.
A single-cell analysis framework allows for characterization of CSF leukocytes and their tissue of origin in multiple sclerosis
Authors: Patrick Ostkamp, Marie Deffner, Andreas Schulte-Mecklenbeck, Christian Wünsch, I-Na Lu, Gregory F. Wu, Susan Goelz, Philip L. De Jager, Tanja Kuhlmann, Catharina C. Gross, Luisa Klotz, Gerd Meyer zu Hörste, Heinz Wiendl, Tilman Schneider-Hohendorf, Nicholas Schwab
Journal: Science Translational Medicine (2022)

Peripheral central nervous system (CNS)–infiltrating lymphocytes are a hallmark of relapsing-remitting multiple sclerosis. Tissue-resident memory T cells (T RM ) not only populate the healthy CNS parenchyma but also are suspected to contribute to multiple sclerosis pathology. Because cerebrospinal fluid (CSF), unlike CNS parenchyma, is accessible for diagnostics, we evaluated whether human CSF, apart from infiltrating cells, also contains T RM cells and CNS-resident myeloid cells draining from the parenchyma or border tissues. Using deep generative models, we integrated 41 CSF and 14 CNS parenchyma single-cell RNA sequencing (scRNAseq) samples from eight independent studies, encompassing 120,629 cells. By comparing CSF immune cells collected during multiple sclerosis relapse with cells collected during therapeutic very late antigen–4 blockade, we could identify immune subsets with tissue provenance across multiple lineages, including CNS border–associated macrophages, CD8 and CD4 T RM cells, and tissue-resident natural killer cells. All lymphocytic CNS-resident cells shared expression of CXCR6 but showed differential ITGAE expression (encoding CD103). A common signature defined CD4 and CD8 T RM cells by expression of ZFP36L2 , DUSP1 , and ID2 . We further developed a user interface–driven application based on this analysis framework for atlas-level cell identity transfer onto new CSF scRNAseq data. Together, these results define CNS-resident immune cells involved in multiple sclerosis pathology that can be detected and monitored in CSF. Targeting these cell populations might be promising to modulate immunopathology in progressive multiple sclerosis and other neuroinflammatory diseases.
Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: A phase I, “window-of-opportunity” study
Authors: Victor Moreno, Juan Manuel Sepúlveda, David A Reardon, Ángel Pérez-Núñez, Pedro González León, Bishoy Hanna, Ellen Filvaroff, Ida Aronchik, Henry Chang, Barbara Amoroso, Marlene Zuraek, Tania Sanchez-Perez, Cristina Mendez, Daniel Stephens, Zariana Nikolova, Michael A Vogelbaum
Journal: Neuro-Oncology (2022)

Abstract Background The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection. Methods Patients received trotabresib 30 mg/day on days 1–4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity. Results Twenty patients received preoperative trotabresib and underwent resection with no delays or cancelations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Six-month progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30. Conclusions Trotabresib penetrates the blood–brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840).
m<sup>6</sup>A reader hnRNPA2B1 drives multiple myeloma osteolytic bone disease
Authors: Rui Liu, Yuping Zhong, Rui Chen, Chengchao Chu, Gang Liu, Yong Zhou, Yazhu Huang, Zhihong Fang, Huan Liu
Journal: Theranostics (2022)

Rationale: Bone destruction is a hallmark of multiple myeloma (MM) and affects more than 80% of patients.Although previous works revealed the roles of N 6 -methyladenosine (m6A) reader hnRNPA2B1 in the development of tumors, whether hnRNPA2B1 regulates bone destruction in MM is still unknown.Methods: Alizarin red S staining, TRAP staining, ELISA and quantitative real-time PCR assays were used to evaluate osteogenesis and osteoclastogenesis in vitro.X ray and bone histomorphometric analysis were preformed to identify bone resorption and bone formation in vivo.Exosome isolation and characterization were demonstrated by transmission electron microscopy, dynamic light scattering, immunofluorescence and flow cytometry assays.The interactions between hnRNPA2B1 and primary microRNAs were examined using RNA pull-down and RIP assays.Coimmunoprecipitation assay was used to test the interaction between hnRNPA2B1 and DGCR8 proteins.Luciferase assay was established to assess miRNAs target genes.Results: Here we show that myeloma cells hnRNPA2B1 mediates microRNAs processing and upregulates miR-92a-2-5p and miR-373-3p expression.These two microRNAs are transported to recipient monocytes or mesenchymal stem cells (MSCs) through exosomes, leading to activation of osteoclastogenesis and suppression of osteoblastogenesis by inhibiting IRF8 or RUNX2.Furthermore, clinical studies revealed a highly positive correlation between the level of myeloma cells hnRNPA2B1 and the number of osteolytic bone lesions in myeloma patients.Conclusions: This study elucidates an important mechanism by which myeloma-induced bone lesions, suggesting that hnRNPA2B1 may be targeted to prevent myeloma-associated bone disease.
Efficacy of supermarket and web-based interventions for improving dietary quality: a randomized, controlled trial
Authors: Dylan L. Steen, Robert N. Helsley, Deepak L. Bhatt, Eileen C. King, Suzanne S. Summer, Matthew Fenchel, Brian E. Saelens, Mark H. Eckman, Sarah C. Couch
Journal: Nature Medicine (2022)

Abstract Dietary interventions may best be delivered at supermarkets, which offer convenience, accessibility, full food inventories and, increasingly, in-store registered dietitians, online shopping and delivery services. In collaboration with a large retail supermarket chain, we conducted a multisite supermarket and web-based intervention targeting nutrition trial (no. NCT03895580), randomizing participants ( n = 247 (139 women and 108 men)) 2:2:1 to two levels of dietary education (Strategy 1 and Strategy 2) or an enhanced control group that included educational components beyond the routine standard of care. Both Strategies 1 and 2 included individualized, in-person, dietitian-led, purchasing data-guided interventions. Strategy 2 also included online tools for shopping, home delivery, selection of healthier purchases, meal planning and healthy recipes. The primary endpoint was change in dietary approaches to stop hypertension (DASH) score (a measure of adherence to the DASH diet) from baseline to 3 months. The primary endpoint was met because, at 3 months, the DASH score increased by 4.7 more for the combined Strategy 1 and Strategy 2 groups than for the control group (95% confidence interval (CI) (0.9, 8.5), P = 0.02). In a prespecified hierarchical test, at 3 months, DASH score increased by 3.8 more for the Strategy 2 group than for the Strategy 1 group (95% CI (0.8, 6.9), P = 0.01). This trial demonstrates the efficacy of data-guided, supermarket-based, dietary interventions and modern online shopping tools in improving dietary quality in a free-living, community-based population. The trial also demonstrates the opportunity for academic investigators to collaborate with retailers to design and rigorously test comprehensive healthcare interventions.
Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later
Authors: Emma C. Milligan, Katherine Olstad, Caitlin A. Williams, Michael Mallory, Patricio Cano, Kaitlyn A. Cross, Jennifer E. Munt, Carolina Garrido, Lisa Lindesmith, Jennifer Watanabe, Jodie L. Usachenko, Lincoln Hopkins, Ramya Immareddy, Yashavanth Shaan Lakshmanappa, Sonny R. Elizaldi, Jamin W. Roh, Rebecca L. Sammak, Rachel E. Pollard, JoAnn L. Yee, Savannah Herbek, Trevor Scobey, Dieter Miehlke, Genevieve Fouda, Guido Ferrari, Hongmei Gao, Xiaoying Shen, Pamela A. Kozlowski, David Montefiori, Michael G. Hudgens, Darin K. Edwards, Andrea Carfi, Kizzmekia S. Corbett, Barney S. Graham, Christopher B. Fox, Mark Tomai, Smita S. Iyer, Ralph Baric, Rachel Reader, Dirk P. Dittmer, Koen K.A. Van Rompay, Sallie R. Permar, Kristina De Paris
Journal: Science Translational Medicine (2022)

The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine.
Airflow limitation and mortality during cancer screening in the National Lung Screening Trial: why quantifying airflow limitation matters
Authors: Robert P Young, Ralph C Ward, Raewyn J Scott, Greg D Gamble, Gerard Silvestri
Journal: Thorax (2022)

Importance Current eligibility criteria for lung cancer (LC) screening are derived from randomised controlled trials and primarily based on age and smoking history. However, the individual benefits of screening are highly variable and potentially attenuated by co-morbidities such as advanced airflow limitation (AL). Objective To examine the relationship between the presence and severity of AL and screening outcomes. Methods This was a secondary analysis of 18 463 high-risk smokers, a substudy from the National Lung Screening Trial, who underwent pre-bronchodilator spirometry at baseline and median follow-up of 6.1 years. We used descriptive statistics and a competing risk proportional hazards model to examine differences in screening outcomes by chronic obstructive pulmonary disease severity group. Results The risk of developing LC increased with worsening AL (effect size=0.34, p&lt;0.0001), as did the risk of dying of LC (effect size=0.35, p&lt;0.0001). While those with severe AL (Global Initiative for Obstructive Lung Disease, GOLD grade 3–4) had the highest risk of LC and the highest LC mortality, they also had fewer adenocarcinomas (effect size=−0.20, p=0.008) and a lower surgery rate (effect size=−0.16, p=0.014) despite comparable staging, and greater non-LC mortality relative to LC mortality (effect size=0.30, p&lt;0.0001). In participants with no AL, screening with CT was associated with a significant reduction in LC deaths relative to chest X-ray (30.3%, 95% CI 4.5% to 49.2%, p&lt;0.05). The clinically relevant but attenuated reduction in those with AL (18.5%, 95% CI −8.4% to 38.7%, p&gt;0.05) could be attributed to GOLD 3–4, where no appreciable mortality reduction was observed. Conclusion Despite a greater risk of LC, severe AL was not associated with any apparent reduction in LC mortality following screening.
Loss of <scp>PP4</scp> contributes to diesel exhaust particles‐induced epithelial barrier integrity disruption and alarmins release
Authors: Feng‐Ming Yang, Meng‐Chun Hu, Chih‐Ming Weng, Hsiao‐Chi Chuang, Yu‐Ting Lan, Bing‐Hua Su, Kyung‐Sun Heo, Han‐Pin Kuo
Journal: Allergy (2022)

Appendix S1 Figures S1-S9 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial
Authors: Shukui Qin, Zhendong Chen, Weijia Fang, Zhenggang Ren, Ruocai Xu, Baek-Yeol Ryoo, Zhiqiang Meng, Yuxian Bai, Xiaoming Chen, Xiufeng Liu, Juxiang Xiao, Gwo Fuang Ho, Yimin Mao, Xin Wang, Jieer Ying, Jianfeng Li, Wenyan Zhong, Yu Zhou, Abby B. Siegel, Chunyi Hao
Journal: Journal of Clinical Oncology (2022)

We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC).
Analysis and therapeutic targeting of the EP300 and CREBBP acetyltransferases in anaplastic large cell lymphoma and Hodgkin lymphoma
Authors: Wei Wei, Zhihui Song, Masahiro Chiba, Wenjun Wu, Subin Jeong, Jing-Ping Zhang, Marshall E. Kadin, Masao Nakagawa, Yibin Yang
Journal: Leukemia (2022)